Carbon monoxide (CO) is the most commonly encountered environmental poison. Paradoxically, more than half a century ago, it was found that carbon monoxide is constantly formed in humans in small quantities, and that under certain pathophysiological conditions this endogenous production of carbon monoxide may be increased (Sjostrand, Scan J Clin Lab Invest. (1949) 1: 201-214). Thus, although it has been known for a long time that carbon monoxide is generated in the human body, only in recent years have scientists begun to explore the possible biological activities of this gaseous molecule. The main endogenous source of carbon monoxide is heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Heme serves as substrate for HO-1 and HO-2 in the formation of carbon monoxide, free ferrous iron, and biliverdin, the latter being rapidly converted to bilirubin by biliverdin reductase (see, e.g., Maines, Annu Rev Pharmacol Toxicol. (1997) 37:517-554). It is generally believed that HO-1 represents a pivotal inducible defensive system against stressful stimuli, including UVA radiation, carcinogens, ischemia-reperfusion damage, endotoxic shock, and several other conditions characterized by production of oxygen-derived free radicals (see, e.g., Abraham et al., Cell Physiol Biochem. (1996) 6: 129-168). As part of its physiological and cytoprotective actions, heme oxygenase-derived carbon monoxide appears to play a major role as neurotransmitter, regulator of sinusoidal tone, inhibitor of platelet aggregation, and suppressor of acute hypertensive responses. Exogenously applied carbon monoxide has been a very useful experimental procedure to reveal the beneficial effects of carbon monoxide in animal disease models (see, e.g., US 2002155166, US 2003039638, US 2003219496, US 2003219497, US 2004052866, WO 03/103585, WO 04/043341). Thus, consistent findings reveal a series of important cellular functions that support a versatile role for carbon monoxide.
Carbon monoxide administration by inhalation is not practical for clinical applications, as it requires special delivery devices such as ventilators, face masks, tents, or portable inhalers. Moreover, carbon monoxide delivery to therapeutic targets by inhalation is inefficient, because it involves transport of carbon monoxide by hemoglobin. Hemoglobin binds carbon monoxide reversibly, but with very high affinity. Therefore, the doses required to deliver carbon monoxide to therapeutic targets in diseased tissues are likely to be associated with adverse effects. Carbon monoxide releasing molecules (CO-RMs) is a potential therapeutic alternative that can deliver carbon monoxide directly to therapeutic targets without the formation of intermediate CO-hemoglobin complexes (see, e.g., Johnson et al., Angew Chem Int Ed Engl (2003) 42:3722-3729). The advantages of carbon monoxide delivery by CO-RMs over carbon monoxide delivery by inhalation is generally recognized. However, CO-RMs should be able to deliver carbon monoxide selectively to diseased tissues. The identification of CO-RMs that are best suited for the treatment of a particular disease remains a major challenge of CO-RM development. Thus, there continues to remain a need for CO-RMs which, upon administration in vivo, selectively target a particular disease or organ with therapeutic benefit.